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Skin hyperpigmentation represents a common aesthetic and dermatological concern, often resulting from excessive melanin synthesis and oxidative stress. Effective skin-lightening strategies target these processes by inhibiting tyrosinase activity, modulating melanogenic regulators, and enhancing antioxidant defenses. Ursolic acid, a natural triterpene abundant in apple peel, has shown potential as a safe and multifunctional skin-brightening molecule. In this study, an apple oil extract rich in ursolic acid (Annurca Apple Oleolite, AAO) was developed and standardized to 784.40 ± 7.58 µg/mL. The extract demonstrated significant tyrosinase inhibition and a marked reduction in melanin content in A375 melanoma cells, accompanied by downregulation of TYRP-1, TYRP-2, and MITF expression and modulation of oxidative stress markers. These molecular effects were confirmed in a randomized, double-blind, placebo-controlled clinical trial involving 42 subjects with hyperpigmented skin. Topical application of a formulation containing 2.5% AAO for 28 days significantly reduced UV and brown spot scores (–6.4% and − 4.1%, respectively; p  < 0.001), decreased melanin index (–10.2%, p  < 0.001), and improved skin brightness and tone uniformity (ITA° +12.4%; L* +3.1%; both p  < 0.001) compared with placebo. Overall, the results highlight AAO as a promising natural agent for managing skin hyperpigmentation through multiple mechanisms, suggesting its potential utility in both cosmetic and dermatological formulations.

Thymic epithelial tumors (TETs) are rare malignancies frequently associated with autoimmunity. However, circulating immune biomarkers for patient stratification and disease monitoring remain undefined. Innate lymphoid cells (ILCs) are emerging regulators of tumor immunity, but their role in TETs has not yet been characterized. Peripheral blood samples from 32 patients with histologically confirmed TETs and 20 healthy donors were analyzed by multiparametric flow cytometry to quantify circulating ILC subsets. Serum cytokine concentrations were measured using multiplex immunoassays. Patients were stratified according to histology, disease activity, and presence of autoimmune manifestations. TETs displayed a significant expansion of circulating ILCs, mainly driven by an enrichment of ILC1, which was more pronounced in patients with active disease and in those with thymic carcinoma. Serum IL-18 levels were elevated-particularly in thymic carcinoma-and correlated with higher concentrations of type 2 cytokines (IL-4, IL-5, IL-9, IL-13). No concomitant increase in canonical ILC1 effector cytokines, including IFN-γ, was observed, indicating a functional dissociation between ILC1 expansion and their expected cytokine profile. These findings delineate a distinct systemic immune signature in TETs, characterized by IL-18 upregulation and altered ILC1 dynamics, with potential implications for immune regulation and autoimmunity. Circulating ILC profiling combined with IL-18 measurement may represent a promising approach for patient stratification, disease monitoring, and the development of novel immunomodulatory strategies in TETs.

Eucalyptus species have been widely employed in the projects of reforestation in Tunisia. Although their ecological functions are controversial, these plants are indeed important to counteract soil erosion, and represent a fast-growing source of fuelwood and charcoal wood. In the present study, we considered five Eucalyptus species, namely Eucalyptus alba, E. eugenioides, E. fasciculosa, E. robusta, and E. stoatei cultivated in the Tunisian Arboreta. The aim was to carry out the micromorphological and anatomical characterization of the leaves, the extraction and phytochemical profile of the essential oils (EOs), and the evaluation of their biological properties. Four of the EOs showed the prevalence of eucalyptol (1,8-cineole) varying from 64.4 to 95.9%, whereas a-pinene predominated in E. alba EO (54.1%). These EOs showed in vitro antioxidant activity, and reduced the oxidative cellular stress as shown by their activity on reactive oxygen species (ROS) production, and modulation of the expression of antioxidant enzymes, such as glutamate-cysteine ligase (GCL) and heme oxygenase-1 (Hmox-1). Moreover, the EOs inhibited the production of nitric oxide (NO), showing anti-inflammatory activity. The data collected suggest that these EOs may be considered a promising therapeutic strategy for inflammation-based diseases and may represent an additional value for the economy of Tunisia.

Marine compounds represent a varied source of new drugs with potential anticancer effects. Among these, sponges, including those belonging to the Irciniidae family, have been demonstrated to exert cytotoxic effects on different human cancer cells. Here, we investigated, for the first time, the therapeutic effect of an extract (referred as iSP) from the sponge, Ircinia ramosa (Porifera, Dictyoceratida, and Irciniidae), on A375 human melanoma cells. We found that iSP impaired A375 melanoma cells proliferation, induced cell death through caspase-dependent apoptosis and arrested cells in the G1 phase of the cell cycle, as demonstrated via both flow cytometry and qPCR analysis. The proapoptotic effect of iSP is associated with increased ROS production and mitochondrial modulation, as observed by using DCF-DHA and mitochondrial probes. In addition, we performed wound healing, invasion and clonogenic assays and found that iSP was able to restrain A375 migration, invasion and clonogenicity. Importantly, we observed that an iSP treatment modulated the expression of the EMT-associated epithelial markers, E-CAD and N-CAD, unveiling the mechanism underlying the effect of iSP in modulating A375 migration and invasion. Collectively, this study provides the first evidence to support the role of Ircinia ramosa sponge extracts as a potential therapeutic resource for the treatment of human melanoma.

Background Prostate cancer (PCa) is the second most common cancer affecting men globally, especially those aged 50 years and above. Despite substantial progress in terms of both prognosis and therapy, PCa remains a significant health concern, necessitating the identification of novel therapeutic targets. Innate lymphoid cells (ILCs) have emerged as critical modulators of tumor immunity, exhibiting both pro- and antitumoral effects. However, little is known yet about their contribution in PCa. This study investigated the phenotypic and functional profiles of ILC subsets in the peripheral blood mononuclear cells (PBMCs) of patients with PCa stratified by Gleason score. Methods PBMCs were isolated by Lymphoprep. ILC frequency and activity were evaluated by flow cytometry. The levels of ILC-activating cytokines were analyzed by multiplex assay in the serum of healthy donors (HDs) and patients with PCa. To evaluate the crosstalk between ILC2s and cancer cells, PC3 and DU145 human PCa cell lines were used. Results We found a stage-dependent increase in the protumoral ILC2 frequency and a concurrent decrease in antitumoral ILC1s in patients with PCa compared with healthy controls. Interestingly, the frequency of ILC2s was higher in patients with elevated prostate-specific antigen (PSA) values, suggesting their potential as molecular predictor for defining the risk category of patients with PCa at diagnosis. Importantly, patients with PCa exhibited hyperactivated ILC2s, characterized by elevated interleukin (IL)-13 and IL-5 production, while ILC1s displayed reduced tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion. Furthermore, serum levels of ILC2-activating cytokines IL-33, IL-18, and prostaglandin D2 (PGD2) were elevated in patients with PCa. In vitro co-culture experiments demonstrated that PCa cell lines, capable of secreting these cytokines, could directly enhance ILC2 activity. Likewise, ILC2-derived IL-13 promoted PCa cell migration and invasion. Conclusions Collectively, our findings highlight a dysregulated ILC profile in PCa, characterized by ILC2 dominance and heightened activity at the expense of ILC1s, suggesting both ILC1s and ILC2s as potential therapeutic targets for PCa treatment. Graphical Abstract

Rosmarinus officinalis L. is an aromatic evergreen plant from the Lamiaceae family. The purpose of this study was to compare the chemical profile and bioactivities of hydroalcoholic extracts derived from wild and cultivated R. officinalis. The chemical composition of the extracts was evaluated via LC–MS analysis, which revealed the presence of a wide range of phenolic compounds, including flavonoids, phenolic and terpenes. Both extracts showed a similar interesting antioxidant activity, probably related to their content of phenol and flavonoids. The analysis of anti-acetylcholinesterase (AChE), anti-butyrylcholinesterase (BChE), and anti-α-amylase activities showed analogous inhibition, except for AChE, in which the wild type was more active than the cultivated one. Finally, in vitro studies were performed using the J774A.1 murine macrophage cell line, to characterize the anti-inflammatory and the antioxidant effects of the extracts. As expected, pretreatment with the extracts significantly reduced the production proinflammatory cytokines and ROS through modulation of the nitric oxide pathway and the mitochondrial activity. Importantly, it is observed that the anti-inflammatory effect of the extracts was explicated through the inhibition of NF-kB and its downstream mediator COX-2. Collectively, these results demonstrated that these extracts could represent a starting point for developing novel therapeutic strategies for the treatment of inflammation-based diseases. Moreover, since no significant changes were observed in terms of composition and activity, both wild and cultivated R. officinalis extracts can be recommended for food and pharmaceutical purposes.

Melanoma is the most dangerous form of skin cancer and is characterized by chemotherapy resistance and recurrence despite the new promising therapeutic approaches. In the last years, erucin (ERU), the major isothiocyanate present in Eruca sativa, commonly known as rocket salads, has demonstrated great efficacy as an anticancer agent in different in vitro and in vivo models. More recently, the chemopreventive effects of ERU have been associated with its property of being a H2S donor in human pancreatic adenocarcinoma. Here, we investigated the effects of ERU in modulating proliferation and inducing human melanoma cell death by using multiple in vitro approaches. ERU significantly reduced the proliferation of different human melanoma cell lines. A flow cytometry analysis with annexin V/PI demonstrated that ERU was able to induce apoptosis and cell cycle arrest in A375 melanoma cells. The proapoptotic effect of ERU was associated with the modulation of the epithelial-to-mesenchymal transition (EMT)-related cadherins and transcription factors. Moreover, ERU thwarted the migration, invasiveness and clonogenic abilities of A375 melanoma cells. These effects were associated with melanogenesis impairment and mitochondrial fitness modulation. Therefore, we demonstrated that ERU plays an important role in inhibiting the progression of melanoma and could represent a novel add-on therapy for the treatment of human melanoma.

Return to sport (RTS), which is understood as return to the pre-injury level, is the key clinical outcome after an anterior cruciate ligament (ACL) injury. However, the continuum for RTS is complex and multifactorial, and no precise and coherent definition describes this process following the surgical reconstruction of ACL. In fact, after the resumption of sports activities, functional asymmetries are recorded, which show a lower ability of the knee to absorb dynamic forces. This occurs because athletes are complex and nonlinear dynamic systems, adaptive, goal-oriented, and constrained by morphology, physiological, psychological and biomechanical factors, activity and environment, with many interacting parts, all of which are capable of affecting the overall results of the system. By applying the theory of dynamic systems (DTS) to biological systems such as athletes, the importance of variability that is present in human movements is highlighted, which reflects the adaptability of the system to the environment. Kinematic variability analysis of the knee, when used during RTS continuum, provides important information about the changes in neuromuscular function that occur after ACL rupture and reconstruction and can be a valuable approach to analyse joint capacity to provide proprioceptive information and how the entire system processes it. To contribute to a clear and unambiguous definition of return to sport, for the functional evaluation of the knee, this study uses nonlinear analysis tools (inertial sensors) and indicators of nonlinear dynamics (LyE), which can represent a new and more adequate functional measurement of this joint in the evaluation of RTS.

Marine compounds represent a varied source of new drugs with potential anticancer effects. Among these, sponges, including those belonging to the Irciniidae family, have been demonstrated to exert cytotoxic effects on different human cancer cells. Here, we investigated, for the first time, the therapeutic effect of an extract (referred as iSP) from the sponge, Ircinia ramosa (Porifera, Dictyoceratida, and Irciniidae), on A375 human melanoma cells. We found that iSP impaired A375 melanoma cells proliferation, induced cell death through caspase-dependent apoptosis and arrested cells in the G1 phase of the cell cycle, as demonstrated via both flow cytometry and qPCR analysis. The proapoptotic effect of iSP is associated with increased ROS production and mitochondrial modulation, as observed by using DCF-DHA and mitochondrial probes. In addition, we performed wound healing, invasion and clonogenic assays and found that iSP was able to restrain A375 migration, invasion and clonogenicity. Importantly, we observed that an iSP treatment modulated the expression of the EMT-associated epithelial markers, E-CAD and N-CAD, unveiling the mechanism underlying the effect of iSP in modulating A375 migration and invasion. Collectively, this study provides the first evidence to support the role of Ircinia ramosa sponge extracts as a potential therapeutic resource for the treatment of human melanoma.

Melanoma is the most dangerous form of skin cancer and is characterized by chemotherapy resistance and recurrence despite the new promising therapeutic approaches. In the last years, erucin (ERU), the major isothiocyanate present in , commonly known as rocket salads, has demonstrated great efficacy as an anticancer agent in different in vitro and in vivo models. More recently, the chemopreventive effects of ERU have been associated with its property of being a H S donor in human pancreatic adenocarcinoma. Here, we investigated the effects of ERU in modulating proliferation and inducing human melanoma cell death by using multiple in vitro approaches. ERU significantly reduced the proliferation of different human melanoma cell lines. A flow cytometry analysis with annexin V/PI demonstrated that ERU was able to induce apoptosis and cell cycle arrest in A375 melanoma cells. The proapoptotic effect of ERU was associated with the modulation of the epithelial-to-mesenchymal transition (EMT)-related cadherins and transcription factors. Moreover, ERU thwarted the migration, invasiveness and clonogenic abilities of A375 melanoma cells. These effects were associated with melanogenesis impairment and mitochondrial fitness modulation. Therefore, we demonstrated that ERU plays an important role in inhibiting the progression of melanoma and could represent a novel add-on therapy for the treatment of human melanoma.